GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer’s disease animal models

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.